1. A novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates inflammatory colonic injury in mice.
- Author
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Funakoshi T, Yamashita K, Ichikawa N, Fukai M, Suzuki T, Goto R, Oura T, Kobayashi N, Katsurada T, Ichihara S, Ozaki M, Umezawa K, and Todo S
- Subjects
- Animals, CD4-Positive T-Lymphocytes drug effects, Chemokine CCL2 drug effects, Chemokine CCL2 metabolism, Colitis chemically induced, Colitis metabolism, Colitis pathology, Dextran Sulfate, HT29 Cells, Humans, Interleukin-12 Subunit p40 drug effects, Interleukin-12 Subunit p40 metabolism, Interleukin-17 metabolism, Interleukin-1beta drug effects, Interleukin-1beta metabolism, Interleukin-6 metabolism, Interleukin-8 drug effects, Interleukin-8 metabolism, Macrophages drug effects, Male, Mice, Mice, Inbred C57BL, NF-kappa B drug effects, RNA, Messenger metabolism, Trinitrobenzenesulfonic Acid, Tumor Necrosis Factor-alpha drug effects, Tumor Necrosis Factor-alpha metabolism, Benzamides pharmacology, Benzamides therapeutic use, Colitis drug therapy, Cyclohexanones pharmacology, Cyclohexanones therapeutic use, Cytokines drug effects, Cytokines metabolism, NF-kappa B antagonists & inhibitors
- Abstract
Background: In inflammatory bowel disease (IBD), gut inflammation is associated with the activation of nuclear factor kappa B (NF-κB), a key pro-inflammatory transcription factor., Aim: To investigate the therapeutic potential of a novel, specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), we examined its effect on IBD using murine experimental colitis models., Methods: The in vitro effect of DHMEQ was evaluated by inflammatory cytokine production and p65 immunostaining using HT-29 and RAW264.7 cells. The in vivo therapeutic effect of DHMEQ was studied in colitis induced by dextran sulphate sodium (DSS) and trinitrobenzenesulphonic acid (TNBS). In these, progression and severity of colitis was mainly assessed by the disease activity index (DAI), histopathology, cellular infiltration, and mRNA expression levels of pro-inflammatory cytokines in the colonic tissues., Results: In RAW264.7 cells, DHMEQ significantly inhibited tumour necrosis factor (TNF)-α and interleukin (IL)-6 production induced by LPS in a dose-dependent manner by blocking the nuclear translocation of NF-κB. In addition, DHMEQ inhibited IL-8 production induced by LPS in HT-29 cells. DHMEQ significantly ameliorated DSS colitis as assessed by DAI scores, colonic oedema, and histological scores. Immunohistochemistry revealed that DHMEQ inhibited colonic infiltration of nuclear p65(+) cells, CD4(+) lymphocytes, and F4/80(+) macrophages. mRNA expression levels of the pro-inflammatory cytokines, such as IL-1β, TNF-α, IL-6, IL-12p40, IL-17, and MCP-1 were also suppressed by DHMEQ administration. Furthermore, DHMEQ significantly ameliorated TNBS colitis as assessed by body-weight changes and histological scores., Conclusion: DHMEQ ameliorated experimental colitis in mice. These results indicate that DHMEQ appears to be an attractive therapeutic agent for IBD., (Copyright © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)
- Published
- 2012
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